Shahan Fernando, MD
Glenn T. Furuta, MD
Over the last three decades, the clinicopathological entity eosinophilic esophagitis (EoE) has emerged as a “new” disease, a disease that is now recognized as one of the major causes of feeding problems in children and of dysphagia and food impaction in adults. Although well-defined patients with EoE were originally reported by Attwood and Straumann in the early 1990s, only recently has the clinical importance of this disease been fully appreciated 1, 2. Evidence of this dramatic change is the rapid increase in publications on this disease; a PubMed search of “eosinophilic esophagitis” or “eosinophilic oesophagitis” reveals that ¾ of the over 1,000 articles in PubMed have been published since 2007 when the original EoE Consensus Recommendations were written 3. We refer the reader to a number of recently published reviews from across the world that fully detail many of the salient features of this disease and its treatment 4-15. Here we present a brief review of important clinical points, identify key differences of this disease between children and adults, relate factors influencing the epidemiology of the disease, share potential relationships that this disease shares with other clinical phenotypes of esophageal eosinophilia, and raise areas of clinical needs that require further investigation.
The intense proliferation of literature since the initial descriptions, and the publication of two Consensus Recommendations 3, 16 and a Clinical guideline 17, provides proof that the scientific and clinical understanding of EoE continue to develop at a rapid pace. Research studies and clinical experiences determined that EoE is a clinicopathological disease requiring both symptoms and abnormal histology to make the diagnosis. Children may present with a wide array of non-specific symptoms including the gradual onset of feeding problems or intermittent episodes of vomiting and abdominal pain; these common problems are often mistaken for GERD and typically do not respond to GERD treatments. Adults present with either solid food dysphagia or food impactions, symptoms that demand identification of an underlying etiology. A number of studies have now shown that EoE is one of the most common underlying etiologies of food impaction. In addition, because of the chronic nature of the disease, children and adults may have developed “coping” behaviors to adapt to their esophageal dysfunction; these behaviors may be missed, as they require additional questioning during the clinical history. Prolonged mealtimes, excessive chewing, avoidance of meats, breads or highly textured foods, and regular use of copious amounts of water or lubricating agents to swallow are not uncommon symptoms that often require elicitation. Endoscopic findings are not pathognomonic and include esophageal rings, furrows, exudates, longitudinal tearing, and strictures. (See Figure 1.) The latter finding may not be evident at the time of endoscopy and require an esophagram to detect. Histologically, the disease is characterized by dense esophageal eosinophilia and marked evidence of epithelial regeneration with basal cell hyperplasia and rete pege elongation. (See Figure 2.) Other causes of esophageal eosinophilia need to be ruled out before assigning a diagnosis of EoE. The natural history of EoE is not fully understood. While EoE is a chronic inflammatory disease, it does not carry pre-malignant potential; strictures and food impactions can occur, but not all EoE patients appear to develop these complications. Treatments include dietary exclusions of food allergens, topical steroids and esophageal dilation.
Figure 1: Endoscopic appearance of eosinophilic esophagitis: Mucosal evidence of active inflammation with white exudates, linear furrows and loss of vascular pattern.
Figure 2: Histological appearance of eosinophilic esophagitis: Representative section of squamous epithelia with dense eosinophilic inflammation, superficial layering of eosinophils, rete pege elongation and basal cell hyperplasia. (Figure courtesy of Kelley Capocelli, M.D.)
Ongoing and past research supports the tenet that EoE occurs when the genetically pre-disposed host encounters an allergic trigger, leading to the production of eosinophil chemokines in the esophageal mucosa, and ultimately driving mucosal eosinophilia. In this regard, gene array and genome wide association studies have identified at least four key molecules strongly associated with EoE. Thymic Stromal Lymphopoietin (TSLP) activates dendritic cells to promote Th2 cell responses, facilitates IgE production, and promotes expansion of basophils; this molecule likely plays a key role in other allergic inflammatory disease such as eczema and asthma. Eotaxin-3 is a potent eosinophil chemoattractant that is increased in EoE patients and when knocked out in animal models, esophageal eosinophilia is diminished. Il-5 and Il-13 play key roles in other atopic diseases and have been shown to participate in EoE in in vitro, in vivo, and translational EoE models. Together, identification of these inflammatory molecules has increased our understanding of the pathogenesis of this disease and points us toward potential future therapeutic targets.
Whether clinical and histological features identified in children and adults represent a continuum that define the natural history of this inflammatory disease or children and adults manifest two different phenotypes is not fully agreed upon 12. Because of developmental differences, children may not be able to fully report symptoms such as dysphagia, thus leading to feeding problems as a primary manifestation. Endoscopic features representative of acute inflammation such as furrows and exudate, appear to be more common in children, whereas those suggestive of chronic inflammation such as rings, strictures, and tears may be more common in adults. While this appears to be a trend, these findings are not exclusively seen in one age group. Histologically, eosinophils remain the hallmark and biomarker of EoE; other features indicative of remodeling and chronic injury have not been definitively shown to be more common in adults or children. Therapeutic efficacies of treatments, whether diet, drug or dilation, do not appear to be different between children or adults, but the adherence to dietary exclusions may be more challenging in older patients.
A number of studies suggest an incidence of EoE of 4 in 10,000 persons. Two observations have consistently emerged regarding the epidemiology of EoE. The first is that regardless of the study, EoE occurs more often in males. The second is that while EoE was once thought to occur primarily in Caucasians in academic centers in the industrialized countries, the scope of this disease clearly continues to expand. Over the last 5 years, case series and prospective studies report clinical experiences with EoE in urban and rural environments, ethnically diverse settings, and an expanding number of countries. Case series from China (proposed incidence/prevelance-0.34%), Saudi Arabia (0.85%), Ireland (0.1%), Korea (6.6%), and Mexico (4%) highlight this geographic variability. Since there is no known mortality associated with EoE and given its chronic nature, it is not surprising that its prevalence is increasing worldwide. Soon et al. recently published a systematic review with meta-analysis demonstrating geographic variations in pediatric population-based incidence and prevalence rates 18.
The chronic nature of EoE is emphasized by several recent studies. The majority (73%) of patients identified with pediatric esophageal eosinophilia had persistent symptoms into adulthood, as well as worse quality of life scores 15 years after the initial diagnosis 19. Additionally, the majority of those patients transitioned to the care of adult gastroenterologists due to esophageal food impactions (40%) and need for endoscopic dilation (14%) from esophageal stricture formation 20.
Several factors may indeed contribute to the increasing prevalence of this disease, such as increasing awareness and recognition of the clinicopathologic characteristics of EoE and increasing procurement of esophageal biopsies 21. Since genes do not change within a few decades, introduction of an environmental factor as a key co-factor in the development of this disease has also been strongly suspected. One speculation is that exogenous exposure of the esophagus to something that breaks the epithelial barrier may allow the underlying pre-disposed Th2 immunomilieu to become activated, thus leading to liberation of eosinophil chemotaxins and resultant eosophageal eosinophilia. This supposition leads one to wonder what these ingested barrier-breaking factors might be and whether they are related to the emerging nature of this disease in locales with changing diets and lifestyles that may predispose to ingesting these products.
With the expanding recognition of esophageal eosinophilia as a histological finding has also come recognition of several other phenotypes that may or may not be pathophysiologically linked. For instance, since the diagnosis of EoE hinges on exclusion of other causes of esophageal eosinophilia, subgroups of patients have been recognized who present clinically as if they have EoE (dysphagia/food impaction), have very dense esophageal eosinophilia (> 15 per HPF), and who clinically and histologically respond to proton pump inhibition. Initially, these patients were thought to have GERD, but as molecular evidence supports an alternative antiinflammatory mechanism of action for PPIs, the term PPI-responsive esophageal eosinophilia (PPIREE) has arisen 22-25. To add further confusion to these observations is the finding that the clinicopathological effect of PPIs may not be sustained over time 26, 27. Whether these groups of patients represent a phenotype of GERD with an exuberant esophageal eosinophilia, EoE that responds to the anti-inflammatory actions of a PPI, or something else is not yet certain. Molecular phenotyping of well-characterized patients, detailed histological descriptions of the esophageal topography as well as clinical responses to therapeutic agents will provide more insights to these questions in the coming years.
With the increased recognition of EoE across the world, a number of questions arise that will not only immediately improve the quality of life of patients with EoE, but also potentially identify novel therapeutic targets. What unique dietary or environmental factors contribute to or prevent the development of EoE? Do genetic patterns remain constant throughout the world? What other clinical phenotypes will be recognized as the natural history of EoE is documented? Careful observations and analyses of patients with esophageal eosinophilia, and answers to these and other questions, will continue to change the face of this fascinating disease.